Gene mutations have been implicated in the etiology of cancer, developmental anomalies, genetic disease and aging. Many different methods for mutation detection have been developed and applied to obtain a more fundamental insight in the chain of molecular events that ultimately lead to mutations. Most of these methods, however, can only be applied to cultured cells and, therefore, do not allow comparative analysis of mutations in various organs and tissues in an intact organism. In order to study gene mutations in all body cells of an experimental animal, we have previously reported the use of bacteriophage lambda-based LacZ transgenic mice for studying, in different organs and tissues, spontaneous or induced mutations. In the current project, these studies will be further extended by using a LacZ plasmId-based transgenic mouse model. Compared to bacteriophage lambda-based systems, the recovery of plasmid vectors from genomic mouse DNA is more efficient and, more importantly, allows detection of a much broader spectrum of mutations. The broad objectives of this proposal are to assess the sensitivity of LacZ plasmid-based transgenic mice to deletion type mutations induced by clastogenic agents. Different dose regimens will be used and the effect of prolonged recovery time of the LacZ transgene on mutation frequency and spectra will be analyzed. Application of this new transgenic mouse mutation model will allow study of the induction of DNA damage, repair, mutagenesis, and carcinogenesis in one animal system. Ultimately, the results obtained will provide us with greater insight into the chain of events that begins with in vivo exposure to genotoxic agents, leads to mutations, and ultimately, results in physiological endpoints.